EP0410813A1 - Anticorps monoclonal contre le BCDF humain et immuno-analyse l'utilisant - Google Patents

Anticorps monoclonal contre le BCDF humain et immuno-analyse l'utilisant Download PDF

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Publication number
EP0410813A1
EP0410813A1 EP90308319A EP90308319A EP0410813A1 EP 0410813 A1 EP0410813 A1 EP 0410813A1 EP 90308319 A EP90308319 A EP 90308319A EP 90308319 A EP90308319 A EP 90308319A EP 0410813 A1 EP0410813 A1 EP 0410813A1
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Prior art keywords
human bcdf
monoclonal antibody
human
bcdf
antibody
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EP90308319A
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German (de)
English (en)
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EP0410813B1 (fr
Inventor
Toshiro c/o Ajinomoto Co.Inc. Shimamura
Yoshiyuki c/o Ajinomoto Co.Inc. Takahara
Hideo Honda
Masataka Yokota
Tadamitsu Kishimoto
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Fujirebio Inc
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Fujirebio Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/248—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • This invention relates to an anti-human BCDF monoclonal antibody and immunoassay for quantifying human BCDF in a sample.
  • Human BCDF also known as human B cell stimulating factor 2 (BSF-2), or interleukin-6 (IL-6), is a biological substance which is closely associated with the immunomodulating system produced by the immunological cells and its entire amino acid sequence has been determined (Nature, vol. 324, p 73, 1980).
  • human BCDF exhibits various biological activities. For example, human BCDF induces the production of antibodies by the activated B cells (Journal of Experimental Medicine, vol. 167, p.332, 1988), and it also induces the differentiation of T cells (Journal of Immunology, vol. 140, p.508, 1988). It is also known that human BCDF induces the synthesis of the acute phase protein emerging in the initial phase of inflammation of liver cells (FEBS Letters, vol. 221, p.18, 1987) and it acts on the blood stem cells to induce the formation of colonies of pluripotent hematopoietic stem cells (Proceedings of National Academy of Science, vol. 84, p.9035, 1987).
  • Atrial myxoma present systemic autoimmune syndromes. It is known that the primary tumor cells in the atrial myxoma produce human BCDF and the autoimmune syndrome of atrial myxoma is improved by removing the primary tumor cells (Proceedings of National Academy of Science, vol. 82, p.5490, 1985). It is also known that the BCDF level of joint fluid in rheumatoid arthritis patients is significantly higher than in normal humans (Medical Immunology, vol. 15, p. 195, 1988), and human BCDF is abnormally produced in the hypertrophic lymph node in Castleman's syndrome (Medical Immunology, vol. 15, p. 197, 1988).
  • human BCDF closely relates to some of the autoimmune diseases. It is also known that in the rejection reaction against a transplanted organ, human BCDF level is temporarily increased immediately before the rejection reaction, that human BCDF level is high in the lesion under inflammation, that tumor cells collected from the patients suffering from a multiple myeloma produce human BCDF and that the growth of the tumor cells is observed by adding human BCDF thereto (Nature, vol. 332, p.83, 1988).
  • human BCDF plays important roles in the immunomodulation in the body, and abnormally high production of human BCDF is closely associated with the above-described autoimmune diseases, inflammation and some cancers.
  • the direction sensitivity is as high as several hundred fg/ml.
  • the test results for determining the human BCDF level in the blood or other biological fluids are affected by various substances in the blood or the biological fluids, so that the methods are difficult to reproduce.
  • the detection sensitivity is too low to detect BCDF in the blood.
  • the human BCDF level in the blood of normal humans is expected to be about 10 pg/ml
  • the sensitivity of conventional immunoassays for quantifying human BCDF is unsatisfactory.
  • polyclonal antibodies are employed as the secondary antibody.
  • the polyclonal antibody is a mixture of a number of antibodies, so that it is impossible to reproduce the same polyclonal antibody with the same properties. Further, a polyclonal antibody cannot be produced in a large amount in one batch and so it is possible to produce the polyclonal antibody on an industrial scale.
  • the human BCDF level can be determined with high sensitivity in samples where the blood contains various substances. Further, since monoclonal antibodies can be produced by culturing hybridomas, and the same monoclonal antibody can be produced repeatedly, the immunoassay system can be produced on an industrial scale while still assuring the identity of the system. To provide such an immunoassay system, at least two anti-human BCDF monoclonal antibodies in which the corresponding epitopes are different are necessary.
  • one object of the present invention is to provide an anti-human BCDF antibody with high specificity in which the epitope is different from that recognized by a conventional anti-human BCDF monoclonal antibody.
  • Another object of the present invention is to provide an immunoassay utilizing the anti-human BCDF monoclonal antibody of the present invention.
  • the present inventors urgently attemmpted to succeed in obtaining an anti-human BCDF antibody with high specificity, one which recognizes an epitope which is different from that recognized by the conventional anti-­human BCDF monoclonal antibodies.
  • the present invention provides an anti-­human BCDF monoclonal antibody which specifically binds to human BCDF, recognizing an epitope which is different from that recognized by anti-human BCDF monoclonal antibodies MH166 and ⁇ BSF2-77, and which neutralizes the human BCDF activities.
  • the present invention also provides an immunoassay for determining human BCDF level in a sample comprising reacting human BCDF with the anti-human BCDF monoclonal antibody of the present invention and determining the amount of human BCDF specifically bound to said anti-­human BCDF monoclonal antibody.
  • a novel anti-human monoclonal antibody having high specificity which recognizes an epitope that is different from that recognized by the conventional anti-human BCDF monoclonal antibodies. Since the anti-human BCDF monoclonal antibody of the present invention has high specificity to human BCDF, and since it recognizes an epitope that is different from that recognized by the conventional anti-human monoclonal antibodies, an immunoassay system was provided for quantifying human BCDF in a sample which utilizes two anti-human BCDF monoclonal antibodies. Thus, by the present invention, a highly sensitive immunoassay system was provided for quantifying human BCDF, which is reproducible on an industrial scale. The present invention greatly contributes to the diagnosis and monitoring of the diseases associated with human BCDF, as well as to the treatment of such diseases.
  • the anti-human monoclonal antibody of the present invention has the following properties:
  • Examples of the anti-human BCDF monoclonal antibody of the present invention include HH61-8 and HH61-10 which were actually obtained in the working examples described below and which are deposited with Fermentation Research Institute of Japan in accordance with Budapest Treaty under the accession numbers FERM BP-3029 and FERM BP 3030, respectively.
  • the monoclonal antibodies HH61-8 and HH61-10 have the following properties:
  • the epitope recognized by the anti-human monoclonal antibody of the present invention is different from that recognized by conventional anti-human BCDF monoclonal antibodies, it is apparent that the monoclonal antibody of the present invention is different from the conventional anti-human BCDF monoclonal antibodies.
  • the monoclonal antibody of the present invention may be prepared based on the so-called hybridoma method, well-known in the art, in which a hybridoma producing the monoclonal antibody of the present invention is cultured and the monoclonal antibody is recovered therefrom.
  • the hybridoma may be prepared by hybridizing a myeloma cell and an antibody-producing cell.
  • the antibody-producing cell may be obtained by immunizing an animal such as mouse or rat with human BCDF and recovering antibody-producing cells, such as spleen cells or lymphocytes, from the immunized animal.
  • the human BCDF to be administered to the animal may be recombinant human BCDF produced by a microorganism such as E. coli , or one produced by human tonsil monocyte or human peripheral blood monocyte or human tumor cells such as human T lymphoma, or may be one produced by an artificially prepared hybridoma.
  • the method of recovering antibody-producing cells from the animal is well-known in the art.
  • the antibody-producing cells collected from the animal immunized with human BCDF are then hybridized with myeloma cells.
  • myeloma cells Although the species of the animal from which the myeloma cell originated may be different from the species of the animal employed for the immunization, better results are usually obtained when the same species is used.
  • An example of the preferred hybridoma for producing the monoclonal antibody of the present invention is a hybridoma between a mouse lymphoma or mouse spleen cell and a mouse myeloma cell.
  • a hybridoma between an antibody-producing lymphoma of BALB/c mouse immunized with human BCDF emulsified with Freund's complete adjuvant and mouse myeloma cell P3-X63-Ag8-U1 is preferred, as shown in the working examples described below.
  • 8-azaguanine resistant myeloma cells such as mouse P3-X63-Ag8 cell, mouse P3-NSI/1-Ag4-1 cell, mouse MPC11-45.6.TG.1.7 cell, mouse SP2/V-Ag14 cell, mouse X63-Ag8-6.5.3, rat 210.RCY.Agl.2.3 cell, human SK0-007 cell and human GH15006TG-A12 cell, all of which are well-known in the art, may also be employed.
  • the method of hybridization of the antibody-producing cell and the myeloma cell which utilizes polyethyleneglycol or Sendai virus (HVJ), is well-known in the art.
  • the cells are cultured in a HAT medium in which only hybridomas can survive so as to select the hybridomas.
  • This culture is usually carried out in a 96-well microtiter plate.
  • the hybridoma producing anti-human BCDF monoclonal antibody may be selected by checking the culture supernatant for the existence of the anti-human BCDF antibody. Checking is done by an immunoassay such as enzyme immunoassay utilizing the specific binding reaction between the antibody and human BCDF.
  • the anti-human BCDF monoclonal antibody of the present invention may be purified from the culture supernatant of the thus selected hybridoma by a conventional method such as salting out and ion-exchange chromotography.
  • the hybridoma may be transplanted into the abdomen of a histocompatible animal such as nude mouse or the like, and the monoclonal antibody may be recovered from the abdominal fluid.
  • the present invention also provides an immunoassay for determining human BCDF level in a sample in which the monoclonal antibody of the present invention is specifically reacted with the human BCDF in the sample.
  • the monoclonal antibody of the present invention may be employed in any immunoassay for quantifying human BCDF.
  • the immunoassay uses a so-called sandwich method in which two anti-human monoclonal antibodies have corresponding epitopes which are different.
  • the sandwich immunoassay employing the monoclonal antibody of the present invention and a conventional anti-human BCDF monoclonal antibody may be carried out, for example, as follows.
  • the anti-human BCDF monoclonal antibody of the present invention serving as a first antibody is fixed on the surface of a well. After blocking the surface of the well with a protein such as BSA, so as to prevent the non-specific binding, a sample which may contain human BCDF is placed in the well. After allowing it to react, the sample fluid is discarded and the well is washed. Then, labelled conventional anti-human monoclonal antibody such as MH166 or ⁇ BSF-2 serving as a second antibody is added to the well and the well is then washed.
  • a protein such as BSA
  • any conventional labelling such as labelling with radiosotope or enzyme, may be employed for labelling the second antibody.
  • the amount of the human BCDF may be determined. It should be noted that the conventional anti-human BCDF monoclonal antibody may be fixed on the well, and the monoclonal antibody of the present invention may be used as the secondary antibody.
  • the anti-human BCDF monoclonal antibody of the present invention may be used, in addition to the immunoassay, for immunohistochemical staining. This may be accomplished by employing an indirect enzyme antibody technique. That is, for example, after fixing a section of topical tissue under inflammation as a smear sample, the sample is blocked with a protein such as BSA so as to prevent the non-specific binding of the antibody, and anti-human BCDF monoclonal antibody of the present invention is then reacted with the sample. Then the sample is treated with a peroxidase-labelled anti-mouse Ig antibody and the resultant is left to stand to allow the reaction. After washing, the sample is then treated with 3,3-diaminobenzidine and hydrogen peroxide so as to color the sample. After treatment, the cells containing human BCDF therein are stained in brown.
  • an indirect enzyme antibody technique That is, for example, after fixing a section of topical tissue under inflammation as a smear sample, the sample is blocked with a protein such as B
  • the anti-human monoclonal antibody of the present invention may also be used as a reagent for recovering human BCDF.
  • the anti-human BCDF monoclonal antibody of the present invention is fixed on an appropriate support, such as resin, and affinity chromatography may be carried out using the antibody-­bound resin.
  • the anti-human BCDF monoclonal antibody of the present invention may be fixed on a cellulose support activated with cyanogen bromide (commercially available from Pharmacia) and the support is then packed in a column so as to provide an affinity column.
  • cyanogen bromide commercially available from Pharmacia
  • the monoclonal antibody of the present invention since the monoclonal antibody of the present invention is capable of neutralizing the human BCDF activities, the monoclonal antibody of the present invention may be used for treating the autoimmune diseases, inflammation and some cancers in which the human BCDF participates.
  • F(ab′)2 fragment prepared by removing Fc region from the anti-human BCDF monoclonal antibody of the present invention by an enzyme, may possibly also be used in the above-mentioned uses in place of the monoclonal antibody of the present invention.
  • a chimera antibody in which the Fc region of the anti-human BCDF monoclonal antibody of the present invention is exchanged with human Fc region may possibly also be used in place of the monoclonal antibody of the present invention.
  • a BALB/c mouse male, 8 weeks old was immunized intraperitoneally with 2 - 3 ⁇ g of purified human BCDF produced by E. coli , which was admixed with equivolume Freund's complete adjuvant. The mouse was immunized another 4 - 6 times with the same antigen composition, and then its spleen was collected. A spleen cell suspension was prepared and the spleen cells were hybridized with P3-X63-Ag8-U1 (P3U1) by the conventional polyethyleneglycol method.
  • hybridized cells were suspended in HAT medium and the suspension was separately placed in wells of a 96-well microtiter plate (commercially available from Corning Glass) with a population density of 2.5 x 105 cells/well.
  • the culture supernatants in the wells in which growth of hybridomas was recognized were examined for the production of anti-human BCDF monoclonal antibody by the hybridomas by the following method: That is, recombinant human BCDF (2 ⁇ g/ml) produced by E. coli dissolved in PBS was separately placed in the wells of a 96-well microtiter plate, and was left to stand overnight at 4°C so as to fix the human BCDF in the wells.
  • the monoclonal antibody of the present invention recognizes the same epitope as the known anti-human BCDF monoclonal antibodies was examined by the following method: That is, BCDF diluted with PBS to a concentration of 10 ⁇ g/ml was placed in the wells of a 96-well microtiter plate (commercially available from Nunc) in the amount of 100 ⁇ l each and was left to stand overnight at 4°C. The solution in the wells was discarded and PBS containing 0.5% BSA was placed in each well in the amount of 200 ⁇ l/well, followed by being left to stand at room temperature for one hour.
  • each well was washed with PBS-­Tween three times and 100 ⁇ l of 1 mg/ml p-nitrophenol phosphate solution was added to each well.
  • the mixture was left to stand at room temperature until the mixture was appropriately colored, when the absorbance of the mixture at 405 nm was measured.
  • anti-human BCDF monoclonal antibodies HH61-8 or HH61-10 of the present invention were added in the amount of 100 - 0.05 ⁇ g/ml and the mixture was allowed to react for 1 hour at 37°C.
  • SKW6-CL-4 cells which are differentiated to IgM-producing cells in the presence of human BCDF were added in a population density of 1 x 105 cells/ml and the resulting mixture was cultured for 72 hours. The culture supernatant in each well was then recovered and the IgM level was determined by the well-­known enzyme immunoassay.
  • Fig. 1 The results are shown in Fig. 1.
  • Fig. 1 the white circles indicate the results when the monoclonal antibody HH61-8 was used and the black circles indicate the results when the monoclonal antibody HH61-10 was used.
  • Line A indicates the absorbance wherein no monoclonal antibody was added, and Line B indicates the background.
  • monoclonal antibodies HH61-8 and HH61-10 specifically neutralized the human BCDFd activity dose-dependently, and they complete neutralized the human BCDF activity at a concentration of 25 ⁇ g/ml or more.

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EP90308319A 1989-07-28 1990-07-30 Anticorps monoclonal contre le BCDF humain et immuno-analyse l'utilisant Expired - Lifetime EP0410813B1 (fr)

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JP1194334A JP2881311B2 (ja) 1989-07-28 1989-07-28 抗ヒトｂｃｄｆモノクローナル抗体及びそれを用いたヒトｂｃｄｆの定量法
JP194334/89 1989-07-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617126A2 (fr) * 1993-02-17 1994-09-28 Ajinomoto Co., Inc. Polypeptide capable d'inhiber la liaison de l'IL-6 humain à son récepteur
EP0635271A1 (fr) * 1993-07-23 1995-01-25 Société Anonyme dite: IMMUNOTECH S.A. Nouveaux kits thérapeutiques anti-médiateurs protéiques, procédé de préparation et compositions pharmaceutiques les renfermant
WO2008019061A2 (fr) * 2006-08-03 2008-02-14 Vaccinex, Inc. Anticorps monoclonaux anti-il-6 et leurs utilisations
US8188235B2 (en) 2008-06-18 2012-05-29 Pfizer Inc. Antibodies to IL-6 and their uses

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US20080000906A1 (en) 2006-06-30 2008-01-03 Tony Nicosia Flush-mount fuel cap with valve
TW200831528A (en) 2006-11-30 2008-08-01 Astrazeneca Ab Compounds
EP3576790A4 (fr) 2017-02-01 2020-12-23 Yale University Traitement de la résistance aux diurétiques
PE20211196A1 (es) 2018-01-05 2021-07-01 Novo Nordisk As Metodos para tratar inflamacion mediada por il-6 sin inmunosupresion

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0220063A2 (fr) * 1985-10-17 1987-04-29 Dainippon Pharmaceutical Co., Ltd. Anticorps anti-interleukine-1 humaine, méthode pour sa production et son utilisation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399429A1 (fr) * 1989-05-22 1990-11-28 Toray Industries, Inc. Anticorps monoclonal contre l'interleukine-6 humaine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0220063A2 (fr) * 1985-10-17 1987-04-29 Dainippon Pharmaceutical Co., Ltd. Anticorps anti-interleukine-1 humaine, méthode pour sa production et son utilisation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BIOCHEM. BIOPHYS. RES. COMMUN. vol. 165, no. 2, 15 December 1989, New York, USA pages 728 - 734; N. IDA et al.: "Establishment of strongly neutralizing monoclonal antibody to human interleukin-6 and its epitope analysis." *
CLIN. EXP. IMMUNOL. vol. 75, no. 1, January 1989, Oxford, GB pages 93 - 99; N. JACKSON et al.: "Two new IgA1-k plasma cell leukaemia cell lines & JJN-2) which proliferate in response to B cell stimulatory factor 2" *
Derwent accession no. 87-168184 Ý24¨ of JP-A-62102157 (C. KISHIMOTO), publ. 12.5.1987 by Derwent Publications Ltd.,London, GB. Antibody against human B cell differentiation factor etc" *
HYBRIDOMA vol. 8, no. 5, March 1989, New York, USA pages 561 - 567; D. NOVICK et al.: "Monoclonal antibodies for affinity purification of IL-6/IFN-beta2 and forneutralization of HGF activity" *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617126A2 (fr) * 1993-02-17 1994-09-28 Ajinomoto Co., Inc. Polypeptide capable d'inhiber la liaison de l'IL-6 humain à son récepteur
EP0617126A3 (fr) * 1993-02-17 1995-06-21 Ajinomoto Kk Polypeptide capable d'inhiber la liaison de l'IL-6 humain à son récepteur.
US5639455A (en) * 1993-02-17 1997-06-17 Ajinomoto Co., Inc. Immunosuppressant
EP0635271A1 (fr) * 1993-07-23 1995-01-25 Société Anonyme dite: IMMUNOTECH S.A. Nouveaux kits thérapeutiques anti-médiateurs protéiques, procédé de préparation et compositions pharmaceutiques les renfermant
FR2707882A1 (fr) * 1993-07-23 1995-01-27 Immunotech Sa Nouveaux kits thérapeutiques anti-médiateurs protéiques, procédé de préparation et compositions pharmaceutiques les renfermant.
US5559012A (en) * 1993-07-23 1996-09-24 Immunotech Therapeutic, IL-6 antibody kits, and process for their preparation
WO2008019061A2 (fr) * 2006-08-03 2008-02-14 Vaccinex, Inc. Anticorps monoclonaux anti-il-6 et leurs utilisations
WO2008019061A3 (fr) * 2006-08-03 2008-10-09 Vaccinex Inc Anticorps monoclonaux anti-il-6 et leurs utilisations
US7919095B2 (en) 2006-08-03 2011-04-05 Vaccinex, Inc. Anti-IL-6 monoclonal antibodies
US8188235B2 (en) 2008-06-18 2012-05-29 Pfizer Inc. Antibodies to IL-6 and their uses
US8436158B2 (en) 2008-06-18 2013-05-07 Pfizer Inc. Antibodies to IL-6 and their uses
US8846037B2 (en) 2008-06-18 2014-09-30 Pfizer Inc. Antibodies to IL-6 and their uses

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EP0410813B1 (fr) 1996-01-17
DE69024871D1 (de) 1996-02-29
JPH0361496A (ja) 1991-03-18
JP2881311B2 (ja) 1999-04-12
DE69024871T2 (de) 1996-08-14

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